Infusion sets for the delivery of a therapeutic substance to a patient

ABSTRACT

Devices and methods for delivering a therapeutic substance to a patient are provided. Embodiments include infusion sets that include an active agent. Also provided are systems and kits.

RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 13/741,375, filed Jan. 14, 2013, which is a continuation ofU.S. patent application Ser. No. 11/322,166, filed Dec. 28, 2005, nowU.S. Pat. No. 8,353,881, all of which are incorporated herein byreference in their entireties for all purposes.

BACKGROUND OF THE INVENTION

Delivery devices for administering a therapeutic agent to a patient areavailable in a variety of configurations. In one such configuration, adelivery device includes an infusion set to deliver therapeuticsubstances to a patient transcutaneously, e.g., to a target subcutaneoussite. Such infusion sets generally include a cannula that provides atranscutaneous pathway through which a therapeutic substance may beadministered to a patient. The cannula typically includes an insertionneedle for providing an opening in the patient's skin through to placethe cannula transcutaneously; thereafter the needle may be removedleaving the cannula transcutaneously positioned. The therapeuticsubstance desired to be delivered to the patient via the cannula istypically retained in a therapeutic agent source that is connected tothe cannula via flexible tubing.

These and other types of infusion sets may be intended to remain in atranscutaneous position, and to deliver a therapeutic substance to apatient, over a period of time. For example, insulin delivery devicesare often intended to infuse insulin to a patient for a period of time,e.g., about three days, without removal.

Because infusion sets may be used for multiple days, the risk ofinfection at the infusion site exists. This risk is of constant concernto users of such infusion sets and healthcare professionals. The risk ofinfection increases as the time period of use increases, therebylimiting the duration of use of the infusion set and requiring frequentreplacements.

Accordingly, as infusion sets for the delivery of therapeutic substancesto patients continues to be of importance in health management, therecontinues to be an interest in devices and methods that decrease therisk of infection associated with infusion sets. Of particular interestare infusion devices for the delivery of therapeutic substances topatients that decrease the risk of infection and increase the period oftime an infusion set may be left in place to deliver a therapeuticsubstance to a patient.

SUMMARY

The subject invention provides devices and methods for delivering atherapeutic substance to a patient that has minimal risk of infection.Embodiments of the subject invention include extended wear infusion setsand methods of delivering therapeutic substances to patients overextended periods of time, e.g., 3 days or more, e.g., 5 days or more,without replacement of the infusion set during the period.

Embodiments of the subject invention include infusion sets that includean active agent such as an antimicrobial agent and/or anti-scarringagent. In certain embodiments, the active agent may be a time-releaseformulation.

In certain embodiments, one or more active agents may be included tomaintain or increase skin elasticity or turgor around the infusion site,and/or to minimize allergic reaction of the skin around the cannula orskin sensitivity.

Also provided are systems and kits.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an exemplary embodiment of a therapeutic substance deliverydevice that includes an active agent, according to the invention;

FIG. 2 shows an exemplary embodiment of another therapeutic substancedelivery device that includes an integrated analyte monitoring system;

FIG. 3 shows an on-body infusion device directed coupled to a cannula inaccordance with one embodiment;

FIG. 4 shows a refillable infusion device directly coupled to a cannulain accordance with one embodiment;

FIGS. 5A-5B show a dual cannula infusion set configuration in accordancewith still further embodiments of the present invention; and

FIG. 6 shows a block diagram of an exemplary embodiment of an analytemonitoring system using an implantable analyte sensor, according to theinvention.

To facilitate understanding, identical reference numerals may be used,where practical, to designate the same elements which are common todifferent figures.

The figures shown herein are not necessarily drawn to scale, with somecomponents and features being exaggerated for clarity.

DEFINITIONS

Throughout the present application, unless a contrary intention appears,the following terms refer to the indicated characteristics.

When one item is indicated as being “remote” from another, this isreferenced that the two items are at least in different buildings, andmay be at least one mile, ten miles, or at least one hundred milesapart. When different items are indicated as being “local” to each otherthey are not remote from one another (for example, they can be in thesame building or the same room of a building).

“Communicating”, “transmitting” and the like, of information referenceconveying data representing information as electrical or optical signalsover a suitable communication channel (for example, a private or publicnetwork, wired, optical fiber, wireless radio or satellite, orotherwise). Any communication or transmission can be between deviceswhich are local or remote from one another.

“Forwarding” an item refers to any means of getting that item from onelocation to the next, whether by physically transporting that item orusing other known methods (where that is possible) and includes, atleast in the case of data, physically transporting a medium, carryingthe data or communicating the data over a communication channel(including electrical, optical, or wireless).

“Receiving” something means it is obtained by any possible means, suchas delivery of a physical item. When information is received it may beobtained as data as a result of a transmission (such as by electrical oroptical signals over any communication channel of a type mentionedherein), or it may be obtained as electrical or optical signals fromreading some other medium (such as a magnetic, optical, or solid statestorage device) carrying the information. However, when information isreceived from a communication, it is received as a result of atransmission of that information from elsewhere (local or remote).

When two items are “associated” with one another they are provided insuch a way that it is apparent that one is related to the other such aswhere one references the other.

A “computer”, “processor” or “processing unit” are used interchangeablyand each references any hardware or hardware/software combination whichcan control components as required to execute recited steps. For examplea computer, processor, or processor unit includes a general purposedigital microprocessor suitably programmed to perform all of the stepsrequired of it, or any hardware or hardware/software combination whichwill perform those or equivalent steps. Programming may be accomplished,for example, from a computer readable medium carrying necessary programcode (such as a portable storage medium) or by communication from aremote location (such as through a communication channel).

A “memory” or “memory unit” refers to any device which can storeinformation for retrieval as signals by a processor, and may includemagnetic or optical devices (such as a hard disk, floppy disk, CD, orDVD), or solid state memory devices (such as volatile or non-volatileRAM). A memory or memory unit may have more than one physical memorydevice of the same or different types (for example, a memory may havemultiple memory devices such as multiple hard drives or multiple solidstate memory devices or some combination of hard drives and solid statememory devices).

“Reading” signal data from a sensor refers to the detection of thesignal data (such as by a detector or meter) from the sensor. This datamay be saved in a memory (whether for relatively short or longer terms).

It will also be appreciated that throughout the present application,that words such as “cover”, “base”, “front, “back”, “top”, “upper”, and“lower” are used in a relative sense only.

“May” refers to optionally.

When two or more items (for example, elements or processes) arereferenced by an alternative “or”, this indicates that either could bepresent separately or any combination of them could be present togetherexcept where the presence of one necessarily excludes the other orothers.

Any recited method can be carried out in the order of events recited orin any other order which is logically possible. Reference to a singularitem, includes the possibility that there are plural of the same itempresent.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

Before the present invention is described, it is to be understood thatthis invention is not limited to particular embodiments described, assuch may, of course, vary. It is also to be understood that theterminology used herein is for the purpose of describing particularembodiments only, and is not intended to be limiting, since the scope ofthe present invention will be limited only by the appended claims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the invention. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges and is also encompassed within the invention, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, the preferredmethods and materials are now described.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentinvention.

As summarized above, the subject invention generally relates to infusionsets of therapeutic substance delivery devices. The infusion sets of theinvention include an active agent, wherein many embodiments the activeagent includes an antimicrobial agent and/or anti-scarring agent.“Antimicrobial agent” is meant broadly to include any substance ofnatural, synthetic or semi-synthetic origin known or to be discovered,or combination of substances, that kills or at least inhibits the growthof microbes such as one or more of bacteria, fungi, viruses, andparasites. “Anti-scarring agent” is meant broadly to include anysubstance of natural, synthetic or semi-synthetic origin known or to bediscovered, or combination of substances, that eliminates or at leastreduces the production of excessive fibrous (scar) tissue. “Activeagent” is used herein to refer to antimicrobial and/or anti-scarringagent(s) and/or any other agent included to provide desired infusion setproperties. The subject invention is primarily described herein withrespect to insulin delivery for exemplary purposes only, where suchdescription is in no way intended to limit the scope of the invention.The subject invention may find use in the intraperitoneal delivery ofinsulin.

In that at least a portion of the subject infusion sets includes activeagent means that at least some active agent permeates, adheres to, isintegrated into, or otherwise becomes associated with one or more of thecomponents of the infusion sets (or other associated component). Thus,as described in greater detail below, active agent may be largelyassociated with a surface of an infusion set, as in a coating, maypenetrate within or between the material of an infusion set, may becovalently or ionically bound to an infusion set, etc. The nature of theassociation between active agent and the infusion set may depend on theparticular agent used, the type and structure of the infusion set beingtreated, etc.

As described above, in many embodiments the active agent is one or moreantimicrobial agents and/or one or more anti-scarring agents. Otheractive agents may be used in addition to or instead of one or moreantimicrobial agents and/or one or more anti-scarring agents. Examplesof active agents include, but are not limited to: antibacterial agents(e.g., penicillin, mupirocin, erthromycin, polymyxin, silversulfadiazine, cephalosporins, bacitracin, tetracycline, doxycycline,gentamycin, quinolines, neomycin, clindamycin, kanamycin, metronidazole,and the like); antiseptic agents (e.g., iodine, Povidine-iodine,benzalkonium chloride, benzoic acid, chlorhexidine, nitrofurazone,benzoyl peroxide, hydrogen peroxide, hexachlorophene, phenol,resorcinol, cetylpyridinium chloride, and the like); antipathogenicpolypeptides; antifungal agents (e.g., nystatin, ciclopirox,chloroxylenol, triacetin, sulconazole, undecylenic acid, tolnaftate,miconizole, clotrimazole, oxiconazole, griseofulvin, econazole,ketoconozole, and amphotericin B and the like); antiviral agents (e.g.,acyclovir, ribarivin, interferons, and the like); anti-scarring agents(e.g., a cell cycle inhibitor, and the like); anti-inflammatory agents(e.g., triamcilolone, betamethasone, dexamethasone, hydrocortisone, andprednisone; antiparasitic agent such as quinacrine, chloroquine,vidarbine, and the like); analgesic agents (e.g., salicylic acid,acetaminophen, ibuprofen, naproxen, piroxicam, flurbiprofen, morphine,and the like); local anesthetics (e.g., lidocaine, bupivacaine,benzocaine, and the like); immunogens (vaccines, and the like);steroidal and non-steroidal anti-inflammatory drugs and/or peptides, andany combinations thereof. In certain embodiments an antimicrobial agentthat is employed includes nitrofurazone, iodine, silver compounds (forexample, silver nitrate, silver sulfadiazine, and the like), macrolidecompounds (e.g., as described in U.S. Pat. No. 6,946,446), zinccompounds (for example, zinc oxide, and the like), and combinationsthereof.

In certain embodiments, active agent may be combined with one or moreother components. For example, active agent may be formulated intopreparations for use, e.g., for applying to an infusion set, bydissolving, suspending or emulsifying active agent in an aqueous ornonaqueous solvent, with conventional additives such as solubilizers,isotonic agents, suspending agents, emulsifying agents, stabilizers,preservatives, and the like. These preparations are sterile andgenerally free of undesirable matter.

In certain embodiments, active agent may be combined with a penetrationenhancer to optimize local active agent delivery into and through theskin (Ghosh, T. K. et al. (1993), Pharm. Tech. 17(3):72-98; Ghosh, T. K.et al. (1993), Pharm. Tech. 17(4): 62-89; Ghosh, T. K. et al. (1993),Pharm. Tech. 17(5):68-76). The penetration enhancer may be selected tohave one or more of the following properties: pharmacologically inert,non-toxic, and non-allergenic, have rapid and reversible onset ofaction, and be compatible with the therapeutic substance to be deliveredby the infusion set.

Exemplary penetration enhancers include, but are not limited to, ethylalcohol, isopropyl alcohol, octolyphenylpolyethylene glycol, oleic acid,polyethylene glycol 400, propylene glycol, N-decylmethylsulfoxide, fattyacid esters (e.g., isopropyl myristate, methyl laurate, glycerolmonooleate, and propylene glycol monooleate); N-methyl pyrrolidone, andthe like.

Embodiments of the subject infusion sets are extended wear infusion setsin that decreased risk of infection and/or scarring and/or other adverseor otherwise undesirable effects of use, due to the active agentproperties of the infusion sets of the subject invention, enables theinfusion sets to be maintained in a transcutaneous position for anextended period of time, e.g., 3 days or more, e.g., 5 days or more,e.g., 7 days or more. In certain embodiments, the useful duration periodis extended and the frequency of replacement is reduced as compared toconventional infusion sets in which it is recommended that a patientfrequently replace a given infusion set such as every few days.

The subject infusion sets may be used to infuse any therapeutic fluid.In many embodiments, and herein further described for exemplary purposesonly, the active-agent infusion sets are used to infuse insulin and arepart of an insulin pump. In certain embodiments, the subject inventionis employed to deliver insulin in a continuous or programmable dosage toa patient.

FIGS. 1 and 2 show exemplary embodiments of active-agentincluding-devices 10 for delivery of a therapeutic substance to apatient. Device 10 includes an infusion set of tubing 2 in fluidcommunication with a cannula 6. In certain embodiments, tubing may notbe included so that the infusion set may include cannula 6, and may ormay not have one or more other components described herein, but may notinclude tubing. In further describing the invention, an infusion set isdescribed primarily as including both tubing 2 and a cannula 6 forexemplary purposes only, where such description is in no way intended tolimit the scope of the invention.

In the embodiment of FIG. 2, the cannula 6 is integrated with an analytesensing device in that cannula 6 is incorporated in the housing of thetransmitter and/or securement element 4. The sensor monitor may includea separate user interface from device 10 or the user interface may bethe same. Accordingly, in such embodiments a user need only to wear asingle securement element 4, on the patient's body, rather than havingto wear one for the sensor and a separate securement element 4 for thecannula 6.

The cannula 6 and the tubing 2 each include a wall defining an interiorlumen and an exterior surface. The tubing 2 and cannula 6 may befabricated from durable, non-toxic, biocompatible materials that arecompatible with the therapeutic substance to be delivered and which aretypically able to withstand sterilization protocols. For example,cannula 6 and/or tubing 2 may be made of a metal and/or polymericmaterial that is relatively soft and biologically compatible such as,but not limited to, stainless steel, high or low density polyethylene,polypropylene, Nylon, polyurethane, polyimides, silicone, polyvinylchloride, polysulfones, polyfluorocarbons, polyethylene terephthalate,copolymers; or polyester elastomers, and mixtures of the above.

As noted above, a needle (not shown) is often included to facilitate thetranscutaneous placement of the cannula 6. An infusion set securementelement 4 may be included to secure the infusion set to the skin of thepatient during use, and usually is low profile so as to be easilyconcealable under an article of clothing. Element 4 may include adhesiveon a side thereof. In certain embodiments, element 4 is an adhesivepatch such as that may include a backing with an adhesive surface.Materials used as the backing layer may include, but are not limited to,sheets or films of polyolefins, polyesters, polyurethanes, polyvinylalcohols, polyvinyl chlorides, polyvinylidene chloride, polyamides,ethylene-vinyl acetate copolymer (EVA), ethylene-ethylacrylate copolymer(EEA), vinyl acetate-vinyl chloride copolymer, cellulose acetate, ethylcellulose, metal vapour deposited films or sheets thereof, rubber sheetsor films, expanded synthetic resin sheets or films, non-woven fabrics,fabrics, knitted fabrics, paper and foils, and the like. Other backingswill be readily apparent to those skilled in the art.

“Infusion set” is meant to include any structure or combination ofstructures that is used to deliver a therapeutic agent from a source toa patient, where infusion sets include a cannula 6 with or withoutoptional tubing 2 and with or without optional securement element 4 orother structure for maintaining the cannula 6 in place and with orwithout an optional cannula insertion element.

The infusion set is connectable to housing 8, e.g., via a releasable ornon-releasable coupling, together providing therapeutic substancedelivery device 10. Housing 8 retains the therapeutic substance source,e.g., an insulin container, in an interior space. In certainembodiments, the therapeutic substance source may be easily replaceablein the housing 8. Containers suitable for holding therapeutic substancessuch as insulin include instruments of containment that may be used todeliver, place, attach, and/or insert the therapeutic substance into thehousing 8 for administration of the medication to a patient and include,but are not limited to, vials, ampules, tubes, capsules, bottles,syringes and bags.

Housing 8 may be an implantable or external pump, e.g., an insulin pump.Where it is an external pump, it may be configured to be attachable tothe patient or article of clothing of the patient, e.g., wearable on abelt (e.g., in the manner of a pager or cellular telephone or the like)or other article of clothing. The housing 8 includes a processor to pumpinsulin from the reservoir that contains the insulin to the patient, andmay include a processor for determining an appropriate dose of insulinbased on certain inputs such as glucose levels, food intake, insulinlevels, etc. Accordingly, the pump may be adapted to controllablydeliver insulin to the patient under the direction of a processor and/orthe patient or healthcare worker. Housing 8 may also include a glucosemeter for determining the level of glucose from a test strip orcontinuous glucose sensor. For example, in certain embodiments a teststrip port may be included for receiving a test strip. A test strip maybe used to confirm the glucose level prior to insulin delivery, e.g., toconfirm a previously obtained glucose level as a safeguard measure. Incertain embodiments, the pump may be adapted to automatically receive,e.g., wirelessly or using a physical connection, glucose informationfrom a glucose sensor, a portion of which sensor may be transcutaneouslypositioned in the patient. The pump may receive glucose information fromany suitable source, wirelessly or using a physical connection.

Active agent may be included with any component of device 10, and istypically included at least in a patient-contacting component. Forexample, tubing 2 and/or cannula 6 and/or element 4 and/or the needle ofthe infusion set may include active agent.

The active agent-containing component(s) may be the infusion set incertain embodiments, or may be a structure that is positionable near aninfusion site. That is, in certain embodiments active agent may not becarried by an infusion set, but rather may be otherwise applied at orsubstantially near the infusion site.

Active agent employed in the subject invention may be deliveredtransdermally, by a topical route, formulated as applicator sticks,solutions, suspensions, emulsions, gels, creams, ointments, pastes,jellies, paints, powders, and aerosols. Such formulations may beincluded in adhesive patch 4, other transdermal patch or other part ofan infusion set, or may be a separate component. Embodiments may includean active agent in the form of a discrete patch or film or plaster orthe like adapted to remain in intimate contact with the epidermis of therecipient for a period of time. For example, such transdermal patchesmay include a base or matrix layer, e.g., polymeric layer, in whichactive agent is retained and/or an adhesive layer or may be inherentlyadhesive. The base or matrix layer may be operably associated with asupport or backing. Active agents suitable for transdermaladministration may also be delivered by iontophoresis and may take theform of an optionally buffered aqueous solution that includes the activeagent. Suitable formulations may include citrate or bis/tris buffer (pH6) or ethanol/water and contain a suitable amount of active ingredient.

Embodiments may also include administration of active agent via abiodegradable implant active agent delivery device. Such may beaccomplished by employing syringes or the cannula 6 insertion syringe todeposit such a biodegradable delivery device under the skin of asubject. The implants degrade completely, so that removal is notnecessary.

Embodiments may include employing an electrode to deliver active agentto a subject. For example, an electrode may be used that has a smallport at its tip which is connected to a reservoir or pump containingactive agent, which may be the same or different than that whichcontains a therapeutic substance. Such may be delivered via separatelumen of tubing 2 or otherwise. Such an electrode may be included aspart of cannula 6 and/or securement element 4. For example, active agentmay be contained within the pump and delivered via tubing 2 or othertubing. The active agent delivery electrode may be implanted using anysuitable technique such as surgical cut down, laproscopy, endoscopy,percutaneous procedure, and the like. In certain embodiments a reservoiror pump may also be implanted in the subject's body. The active agentdelivery electrode, or other analogous device, may be controllable suchthat the amount of active agent delivered, the rate at which the activeagent may be delivered, and the time period over which the active agentmay be delivered, etc., may be controllable and may be adjusted, e.g.,by a user and/or healthcare worker, or automatically via suitablesoftware/hardware, e.g., by a controller of the pump. As describedabove, at least part of an infusion set may include an active agent. Aninfusion set may include or incorporate active agent thereof in anysuitable manner. At least a portion of the infusion set, e.g., apatient-contacting portion, includes active agent, where in certainembodiments substantially the entire infusion set may include the activeagent. Active agent may be immobilized on a surface of the one or morecomponents of an infusion set or may be configured to diffuse away froman infusion set surface.

In certain embodiments, active agent is a coating on at least a portionof the infusion set, e.g., on a surface of tubing 2 and/or element 4and/or cannula 6 and/or optional needle. In certain embodiments, activeagent is incorporate, e.g., embedded, or otherwise integrated into thematerial of one or more of these components of an infusion set. Forexample, in certain embodiments securement element 4 and/or cannula 6,e.g., outer and/or inner surfaces of the cannula 6, may include activeagent such that the securement element 4 and/or cannula 6 may include acoating thereof such that active agent may be incorporated as a thincoating positioned about a surface of the securement element 4 and/orcannula 6. The amount of active agent to be included may be readilycontrolled by applying multiple thin coats thereof, e.g., and allowingit to dry between coats.

The thickness of a coating will be minimal so as not to appreciablyincrease the thickness of the coating-containing component. In manyembodiments, the thickness is substantially uniform and the active agentis substantially homogenous throughout the area including it.

Alternatively or in addition to a coating, an active agent may beincorporated within the material of an infusion set, e.g., incorporatedwithin the material of tubing 2 and/or patch 4 and/or cannula 6 and/oroptional needle, in most instances resulting in active agent that isdispersed evenly throughout the component(s) of the infusion sets(substantially homogeneously).

Embodiments include infusion sets that have the ability to emit ordiffuse active agent at a controllable rate, e.g., may include acontrolled release, such as a time release, formulation. For example, aninfusion set may include a formulation that is designed to releaseactive agent gradually over time, e.g., over about a period of timecommensurate with a period of time in which an infusion set istranscutaneously positioned in a patient. A controlled releaseformulation may employ a polymer or other non active agent material tocontrol the release of the active agent. The active agent release ratemay be slowed by diffusion through the polymer, or the active agent maybe released as the polymer degrades or disintegrates in the body.

The active agent may be added to the infusion set during fabrication ofan infusion set and/or may be applied to an infusion set after it hasbeen fabricated. For example, a coating containing active agent thereofmay be applied to an infusion set after it has been fabricated.

Active agent may be applied to an infusion set by any of a variety ofmethods, e.g., by spraying the active agent onto the infusion set or bydipping the infusion set into the active agent, by coating the activeagent with a slotted die, or otherwise immersing or flooding an infusionset with the active agent.

The amount of active agent included in an infusion set may varydepending on a variety of factors such as the particular active agentused, the particulars of the infusion set, etc. In any event, aneffective amount of active agent used—an amount sufficient to providethe requisite result, e.g., antibacterial, anti-scarring, and the like,for the desired period of time.

The subject infusion sets may be used with an analyte monitoring systemusing a sensor at least a portion of which is positioned beneath theskin of the user for the in vivo determination of a concentration of ananalyte such as, for example, acetyl choline, amylase, bilirubin,cholesterol, chorionic gonadotropin, creatine kinase (e.g., CK-MB),creatine, DNA, fructosamine, glucose, glutamine, growth hormones,hormones, ketones, lactate, peroxide, prostate-specific antigen,prothrombin, RNA, thyroid stimulating hormone, and troponin. Theconcentration of drugs, such as, for example, antibiotics (e.g.,gentamicin, vancomycin, and the like), digitoxin, digoxin, drugs ofabuse, theophylline, warfarin, and the like, in a body fluid. The sensormay be, for example, subcutaneously positioned in a patient for thecontinuous or periodic monitoring an analyte in a patient's interstitialfluid. This may be used to infer the glucose level in the patient'sbloodstream. Sensors for insertion into a vein, artery, or other portionof the body containing fluid, may also be used. A sensor may beconfigured for monitoring the level of the analyte over a time periodwhich may range from hours, days, weeks, or longer. For example, acontinuous glucose sensing system may be used with an insulin deliverypump that includes an active-agent containing infusion set. At leastsome components of a glucose sensing system may be integrated with aninsulin pump of the subject invention, e.g., as described in U.S. PatentApplication No. 60/664,215, and elsewhere.

FIG. 3 shows an on-body infusion device directed coupled to a cannula inaccordance with one embodiment. Referring to FIG. 3, in one embodiment,a patch pump type infusion device 310 is provided with a cannula 320directed coupled thereto. As can be seen from the figure, cannula 320 isdirectly coupled to on-body infusion device 310 without the use of anyinfusion tubing. In one embodiment, infusion device 310 includes controlmechanism to control the infusion of the therapeutic substance such asinsulin stored, for example, in a reservoir (not shown) in infusiondevice 310 to a patient via cannula 320.

FIG. 4 shows a refillable infusion device directly coupled to a cannulain accordance with one embodiment. As shown in the Figure, cannula 420is coupled to insulin storage device 410 (which may include an infusiondevice or a subcomponent thereof) for delivering a therapeutic substanceto a patient. Cannula 420 is placed under the patient's skin and isconfigured to deliver the therapeutic substance such as insulin to thepatient. In this embodiment, insulin storage device 410 is configured toreceive a predetermined amount of the therapeutic substance to store andsubsequently infuse to a patient, using a syringe, for example. In thismanner, insulin storage device 410 may be configured to receive insulinthrough a self-sealing membrane or any other type of suitable non-porousmembrane, after the placement of cannula 420 under the patient's skin.

FIGS. 5A-5B show a dual cannula infusion set configurations inaccordance with still further embodiments of the present invention.Referring to FIG. 5A, an inner cannula 502 is shown to be substantiallysurrounded by an outer cannula 501, where during the initial placementof the infusion set, both the inner cannula 502 and the outer cannula501 are substantially simultaneously placed under the skin of thepatient. Moreover, as can be seen from FIG. 5A, the inner cannula 502 isplaced at a greater depth under the patient's skin as compared to therelative placement of the outer cannula 501. In this manner, after apredetermined time period of usage has elapsed (for example, about 3days), the inner cannula 502 in one embodiment is withdrawn or retractedfrom the patient, while retaining the outer cannula 501 in the originalplace under the skin of the patient.

Accordingly, the usage time may be extended beyond the typical 3 dayperiod by using outer cannula 501 for insulin infusion, for example,subsequent to the first 3 days. In this manner, the extended usage ofthe infusion set may be desirable further when the infusion systemincluding the infusion device and the infusion set is used inconjunction with a 5 day or 7 day continuous monitoring system such as acontinuous glucose monitoring system.

Referring back to FIG. 5B, in a further embodiment, the dual cannulainfusion set configuration as shown may include an outer cannula 511 anda separate inner cannula 512, where the outer cannula 511 is placed at agreater depth under the patient's skin as compared to the relativeplacement of the inner cannula 512. In this embodiment, as compared tothe embodiment shown in FIG. 5A, the outer cannula 511 is first placedunder the skin during the initial infusion period of for example, 3days. Thereafter, prior to the removal or withdrawal of the outercannula 511, the inner cannula 512 inserted or positioned within theouter cannula 511 and under the patient's skin, though at a less depthas compared to the placement of the outer cannula 511. Thereafter, withthe removal or withdrawal of the outer cannula after the first threedays of usage, the inner cannula 512 may be configured to continuouslydeliver the therapeutic substance such as insulin. In this manner, witha single skin piercing (of the outer cannula 511 placement) and therebyminimizing skin trauma as well as associated pain, the infusion set maybe used for extended time period such as 5 days or 7 days.

In certain embodiments, in addition to, or instead of, an infusion setand/or other associated structure including an active agent, at least aportion of a continuous analyte monitoring system may include activeagent. For example, a portion of an analyte sensor, transmitter mount,and the like, may include an antimicrobial agent and/or anti-scarringagent.

The analyte sensors and analyte monitoring systems of the presentinvention may be utilized under a variety of conditions. The particularconfiguration of a sensor and other units used in an analyte monitoringsystem may depend on the use for which the sensor and system areintended and the conditions under which the sensor and system willoperate. As noted above, embodiments include a sensor configured forimplantation into a patient or user. The term “implantation” is meantbroadly to include wholly implantable sensors and sensors in which onlya portion of which is implantable under the skin and a portion of whichresides above the skin, e.g., for contact to a transmitter, receiver,transceiver, processor, etc. For example, implantation of the sensor maybe made in the arterial or venous systems for direct testing of analytelevels in blood. Alternatively, a sensor may be implanted in theinterstitial tissue for determining the analyte level in interstitialfluid. This level may be correlated and/or converted to analyte levelsin blood or other fluids. The site and depth of implantation may affectthe particular shape, components, and configuration of the sensor.Subcutaneous implantation may be desired, in some cases, to limit thedepth of implantation of the sensor. Sensors may also be implanted inother regions of the body to determine analyte levels in other fluids.Examples of suitable sensors and sensor systems for use in the subjectinvention are described, for example, in U.S. Pat. Nos. 6,175,752,6,284,478, 6,134,461, and elsewhere.

An exemplary embodiment of an analyte monitoring system 40 for use witha medication delivery device 10 is illustrated in block diagram form inFIG. 6. The analyte monitoring system 40 includes, at minimum, a sensor42, a portion of the sensor which is configured for implantation (e.g.,subcutaneous, venous, or arterial implantation) into a patient, and asensor control unit 44. Sensor 42 is coupleable to sensor control unit44 which is typically attachable to the skin of a patient. Sensorcontrol unit 44 operates sensor 42, including, for example, providing avoltage across the electrodes of the sensor 42 and collecting signalsfrom the sensor 42. Sensor control unit 44 may evaluate the signals fromsensor 42 and/or transmit the signals to one or more optionalreceiver/display units 46, 48 for evaluation. Sensor control unit 44and/or receiver/display units 46, 48 may display or otherwisecommunicate the current level of the analyte. Control unit 44 and one ormore optional receiver/display units 46, 48 may be combined in a singleunit or may be separate. Furthermore, sensor control unit 44 and/or thereceiver/display units 46, 48 may indicate to the patient, via, forexample, an audible, visual, or other sensory-stimulating alarm, whenthe level of the analyte is at or near a threshold level. In someembodiments, an electrical shock may be delivered to the patient as awarning through one of the electrodes or the optional temperature probeof the sensor. For example, if glucose is monitored then an alarm may beused to alert the patient to a hypoglycemic or hyperglycemic glucoselevel and/or to impending hypoglycemia or hyperglycemia.

Sensor 42 includes at least one working electrode and a substrate.Sensor 42 may also include at least one counter electrode (orcounter/reference electrode) and/or at least one reference electrode.The counter electrode and/or reference electrode may be formed on thesubstrate or may be separate units. For example, the counter electrodeand/or reference electrode may be formed on a second substrate which isalso implantable in the patient or, for some embodiments of the sensorsthe counter electrode and/or reference electrode may be placed on theskin of the patient with the working electrode or electrodes beingimplanted into the patient. The use of an on-the-skin counter and/orreference electrode with an implantable working electrode is describedin, e.g., U.S. Pat. No. 5,593,852.

On-skin sensor control unit 44 may optionally contain a transmitter ortransceiver (not shown) for transmitting the sensor signals or processeddata from a processing circuit to a receiver (or transceiver)/displayunit 46, 48; to pump 8, a data storage unit (not shown) for temporarilyor permanently storing data; a reference voltage generator (not shown)for providing a reference voltage for comparison with sensor-generatedsignals; and/or a watchdog circuit that monitors the operation of theelectronic components in the on-skin sensor control unit.

One or more receiver/display units 46, 48 may be provided with theanalyte monitoring device 40 for easy access to the data generated bythe sensor 42 and may, in some embodiments, process the signals from theon-skin sensor control unit 44 to determine the concentration or levelof analyte in the subcutaneous tissue. Small receiver/display units 46may be carried by the patient. The receiver may be a transceiver.Receivers may be palm-sized and/or may be adapted to fit on a belt orwithin a bag or purse that the patient carries.

The receiver/display units 46, 48 typically include a receiver toreceive data from the on-skin sensor control unit 44, an analyzer toevaluate the data, a display to provide information to the patient, andan optional alarm system to warn the patient when a condition arises.The receiver/display units 46, 48 may also optionally include a datastorage device, a transmitter, and/or an input device such as a keypador keyboard. The input device 162 may allow numeric or alphanumericinput. The input device 162 may also include buttons, keys, or the likewhich initiate functions of and/or provide input to the analytemonitoring device 40. Such functions may include initiating a datatransfer, inputting calibration data, and/or indicating events toactivate storage of data representative of the event.

The receiver/display units 46, 48 may also include other components suchas a power supply (e.g., a battery and/or a power supply that canreceive power from a wall outlet), a watchdog circuit, a bias currentgenerator, and an oscillator. These additional components are similar tothose described above for the on-skin sensor control unit 44. Thereceiver/display units 46, 48 may also include a number of optionalitems. One item is a data storage unit which may be desirable to storedata for use if the analyzer is configured to determine trends in theanalyte level. The data storage unit may also be useful to store datathat may be downloaded to another receiver/display unit or to a computeror other data storage device in a patient's home, at a doctor's office,etc. for evaluation of trends in analyte levels.

Sensor 42 and the electronic components within the on-skin sensorcontrol unit 44 are coupled via conductive contacts. The one or moreworking electrodes, counter electrode (or counter/reference electrode),optional reference electrode are attached to individual conductivecontacts. The conductive contacts may be provided on the interior of theon-skin sensor control unit 44. Other embodiments of the on-skin sensorcontrol unit 44 have the conductive contacts disposed on the exteriorthereof. The placement of the conductive contacts is such that they arein contact with contact pads on the sensor when the sensor is properlypositioned within the on-skin sensor control unit 44.

In certain embodiments, electrical contacts may be eliminated betweenthe sensor 42 and the on-skin sensor control unit 44. Power may betransmitted to the sensor via inductive coupling, using, for example,closely space antennas (e.g., facing coils) (not shown) on the sensorand the on-skin sensor control unit.

A sensor may be adapted to be a replaceable component in an in vivoanalyte monitor, and particularly in an implantable analyte monitor. Inmany embodiments, the sensor is capable of operation over a period ofdays or more, e.g., a period of operation may be at least about one day,e.g., at least about three days, e.g., at least about one week or more.The sensor may then be removed and replaced with a new sensor.

As noted herein, analyte monitoring system 40 may be coupled with pump10 so that analyte, e.g., glucose, information is automatically sent tothe pump, where such information may be used to determine theappropriate amount of insulin to deliver to the patient, where incertain embodiments system 40 and device 10 may be integrated to providean integrated infusion device and monitoring system.

For example, the subject invention also includes sensor-based medicationdelivery systems. The system may provide a medication such as insulin tocounteract the high or low level of the analyte, e.g., glucose, inresponse to the signals from one or more sensors. Alternatively, thesystem may monitor the glucose concentration to ensure that the insulinremains within a desired therapeutic range. An insulin delivery systemmay include one or more (e.g., two or more) glucose sensors, an on-skinsensor control unit, a receiver/display unit, a data storage andcontroller module, and an insulin administration system, wherein thesensor, insulin pump device, or both, include active agent as describedherein. In some cases, the receiver/display unit, data storage andcontroller module, and insulin administration system may be integratedin a single unit. The sensor-based insulin delivery system uses datafrom the one or more glucose sensors to provide necessary input for acontrol algorithm/mechanism in the data storage and controller module tocontrol and adjust the administration of insulin.

Finally, kits for use in practicing the subject invention are alsoprovided. The subject kits may include an infusion set that includes anactive agent. For example, a kit may include one or more infusion setsas described herein, and/or other structure that includes an activeagent to be used with the infusion set. In certain embodiments, a kitmay include a therapeutic agent delivery device that includes such aninfusion set and a housing for containing a therapeutic substance andcontrolling the delivery of the therapeutic substance to a patient. Inmany embodiments, an insulin pump is included in a kit, the insulin pumpincluding an infusion set having active agent. Embodiments may alsoinclude an analyte sensor (e.g., glucose sensor) such as a continuousanalyte sensor and/or sensor insertion device and/or transmitter and/orreceiver.

In addition to one or more active agent-including infusion sets, thesubject kits may also include written instructions for using theinfusion sets. The instructions may be printed on a substrate, such aspaper or plastic, etc. As such, the instructions may be present in thekits as a package insert, in the labeling of the container of the kit orcomponents thereof (i.e., associated with the packaging orsub-packaging) etc. In other embodiments, the instructions are presentas an electronic storage data file present on a suitable computerreadable storage medium, e.g., CD-ROM, diskette, etc. In yet otherembodiments, the actual instructions are not present in the kit, butmeans for obtaining the instructions from a remote source, e.g. via theInternet, are provided. An example of this embodiment is a kit thatincludes a web address where the instructions can be viewed and/or fromwhich the instructions can be downloaded. As with the instructions, thismeans for obtaining the instructions is recorded on a suitablesubstrate.

In many embodiments of the subject kits, the components of the kit arepackaged in a kit containment element to make a single, easily handledunit, where the kit containment element, e.g., box or analogousstructure, may or may not be an airtight container, e.g., to furtherpreserve the contents of the kit until use.

It is evident from the above results and discussion that theabove-described invention provides active agent-including medicationinfusion devices such as antimicrobial and/or anti-scarring glucosepumps. The above-described invention provides a number ofadvantages—some of which are described above and which include, but arenot limited to, reduced risk of infection and/or scarring and prolongeduse. As such, the subject invention represents a significantcontribution to the art.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

1-20. (canceled)
 21. A method of using an infusion system comprising aninner cannula configured to deliver a medication to a patient and anouter cannula configured to reside over the inner cannula and to deliverthe medication to the patient, wherein the method comprises: positioningthe inner cannula and the outer cannula together under the skin of thepatient; using one of the inner cannula or the outer cannula to deliverthe medication to the patient; withdrawing the used cannula from thepatient while leaving the other cannula within the patient to deliverthe medication; and delivering the medication through the other cannula.22. The method of claim 21, wherein the medication is insulin.
 23. Themethod of claim 22, wherein using one of the inner cannula or the outercannula to deliver the medication to the patient comprises using one ofthe inner cannula or the outer cannula to deliver the insulin intosubcutaneous tissue of the patient.
 24. The method of claim 21,comprising: using the inner cannula to deliver the medication to thepatient; withdrawing the inner cannula from the patient while leavingthe outer cannula within the patient; and then delivering the medicationthrough the outer cannula.
 25. The method of claim 24, wherein the innerand outer cannulas are coupled with an on-body device that is alsocoupled with a sensor, the method comprising: positioning the sensor inthe patient; and sensing an analyte level of the patient with thesensor.
 26. The method of claim 25, wherein the infusion systemcomprises a pump and a sensor control unit in electrical communicationwith the sensor, wherein the pump is configured to automatically receiveinformation indicative of the analyte level from the sensor controlunit.
 27. The method of claim 24, wherein positioning the inner cannulaand the outer cannula together under the skin of the patient comprisespositioning an end of the inner cannula and an end of the outer cannulaunder the skin of the patient, wherein the end of the inner cannula isat a greater depth under the skin than the end of the outer cannula. 28.The method of claim 21, comprising: using the outer cannula to deliverthe medication to the patient; withdrawing the outer cannula from thepatient while leaving the inner cannula within the patient; and thendelivering the medication through the inner cannula.
 29. The method ofclaim 28, wherein the inner and outer cannulas are coupled with anon-body device that is also coupled with a sensor, the methodcomprising: positioning the sensor in the patient; and sensing ananalyte level of the patient with the sensor.
 30. The method of claim29, wherein the infusion system comprises a pump and a sensor controlunit in electrical communication with the sensor, wherein the pump isconfigured to automatically receive information indicative of theanalyte level from the sensor control unit.
 31. The method of claim 28,wherein positioning the inner cannula and the outer cannula togetherunder the skin of the patient comprises positioning an end of the innercannula and an end of the outer cannula under the skin of the patient,wherein the end of the outer cannula is at a greater depth under theskin than the end of the inner cannula.
 32. The method of claim 21,wherein the infusion system further comprises a securement element andan implantable sensor for monitoring an analyte level, the methodcomprising securing the implantable sensor, the inner cannula, and theouter cannula to the patient with the securement element.
 33. The methodof claim 21, wherein the infusion set further comprises tubingconfigured for fluid communication between a source of the medicationand the inner or outer cannula.
 34. The method of claim 21, wherein anactive agent comprising an anti-scarring agent or both an antimicrobialagent and an anti-scarring agent is present on at least one component ofthe infusion system.
 35. The method of claim 34, further comprisingcontrollably releasing the active agent over a predetermined time periodby use of a non-active agent.
 36. The method of claim 35, wherein thenon-active agent comprises a polymer.
 37. The method of claim 36,wherein the polymer partially degrades or disintegrates over thepredetermined time period to release the active agent.
 38. The method ofclaim 35, wherein the non-active agent provides a diffusion layerbetween the patient and the inner or outer cannula.
 39. The method ofclaim 35, wherein the active agent is present on the outer cannula. 40.The method of claim 35, wherein the active agent is present on an outersurface of the outer cannula and on an outer surface of the innercannula.